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NORD is very grateful to James E. Heubi, MD, Professor and Associate Chair for Clinical Research of Pediatrics, Associate Dean for Clinical and Translational Research, Children's Hospital Medical Center /University of Cincinnati College of Medicine, for assistance in the preparation of this report. \
Reye syndrome is a rare disorder of childhood and adolescence. It primarily affects individuals under 18 years of age, particularly children from approximately age four to 12 years. In rare cases, infants or young adults may be affected. The disorder's cause is unknown. However, there appears to be an association between the onset of Reye syndrome and the use of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses, particularly upper respiratory tract infections (e.g., influenza B) or, in some cases, chickenpox (varicella).
Although any organ system may be involved, Reye syndrome is primarily characterized by distinctive, fatty changes of the liver and sudden (acute) swelling of the brain (cerebral edema). Associated symptoms and findings may include the sudden onset of severe, persistent vomiting; elevated levels of certain liver enzymes in the blood (hepatic transaminases); unusually high amounts of ammonia in the blood (hyperammonemia); disturbances of consciousness; sudden episodes of uncontrolled electrical activity in the brain (seizures); and/or other abnormalities, leading to potentially life-threatening complications in some cases. Due to the potential association between the use of aspirin-containing agents and the development of Reye syndrome, it is advised that such medications be avoided for individuals under age 18 years who are affected by viral infections such as influenza or chickenpox.
The symptoms of Reye syndrome typically begin after a viral illness, particularly an upper respiratory infection (e.g, with influenza B virus) or, in some cases, chickenpox (varicella). Less commonly, Reye syndrome may develop after infection with other viral agents, such as influenza A or rubella. (For further information, please see the "Causes" section of this report below.)
About three to five days after the onset of viral infection, affected children experience sudden, persistent, uncontrolled vomiting. Disturbances of consciousness may begin simultaneously or develop within hours. Such abnormalities often include irritability, restlessness, disorientation, lethargy, and memory impairment. In some cases, children may remain lethargic with no progression to unconsciousness. In other cases, neurological deterioration may be rapidly progressive, leading to an apparent lack of awareness of surroundings (stupor); a state of unconsciousness and unresponsiveness (coma); widening (dilation) of the pupils (mydriasis); rapid, shallow breathing (tachypnea); a rapid heart rate (tachycardia); and loss of certain reflexes (e.g., deep tendon, pupillary, oculocephalic). Severe neurological dysfunction may also lead to episodes of uncontrolled electrical disturbances in the brain (seizures); abnormal posturing (decerebrate or decorticate rigidity), indicating damage to certain areas of the brain; and potentially life-threatening complications.
Findings associated with fatty degeneration of the liver may include enlargement of the liver (hepatomegaly) and abnormally increased levels of certain liver enzymes (hepatic transaminases), indicating impaired liver functioning. However, jaundice, a finding often associated with liver dysfunction, generally does not occur (anicteric) or is minimal in those with the disorder. Jaundice is a condition in which there is yellowish discoloration of the skin, eyes, and mucous membranes due to excessive accumulation of the pigment bilirubin in the blood.
In individuals with Reye syndrome, disease severity may be extremely variable. According to reports in the medical literature, some affected individuals may have mild symptoms without disease progression. However, as discussed above, others with the disorder may develop rapid neurological deterioration leading to potentially life-threatening complications. Researchers have proposed a clinical staging system based upon the varying levels of severity, with Grades I, II, and III indicating relatively mild to moderate disease and Grades IV and V signifying more severe disease.
The specific cause of Reye syndrome remains unknown. However, according to researchers, there appears to be an association between the condition's onset and the administration of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses. This typically includes upper respiratory tract infections caused by the influenza B virus or chickenpox (varicella). Less commonly, the development of Reye Syndrome has been reported in association with other viral infections, including influenza A, herpes simplex, rubella, or Epstein-Barr.
The primary symptoms and findings associated with Reye syndrome appear to result from distinctive, fatty changes of the liver, impaired liver functioning, and an abnormal accumulation of fluid in brain tissues (cerebral edema), which may lead to increased fluid pressure and potential compression of brain tissue. In individuals with Reye Syndrome, degenerative changes of the liver are associated with an abnormal infiltration of liver cells (hepatocytes) with fatty compounds (e.g., triglycerides). In addition, to a lesser degree, there may be fatty infiltration of the spleen, the pancreas, voluntary (skeletal) muscles, heart muscle (myocardium), and/or the tubular structures within the kidneys that collect and conduct urine (renal tubules).
Researchers suggest that the primary underlying defect in Reye syndrome is abnormal functioning of mitochondria with reduced activities of liver (hepatic) mitochondrial enzymes (e.g., ornithine transcarbamylase [OTC], carbamyl phosphate synthetase [CPS], pyruvate dehydrogenase [PDH]). However, the cause of such mitochondrial dysfunction remains unknown. Mitochondria are the tiny, rodlike structures (organelles) outside the nuclei of cells that function in cellular metabolism and other processes. They contain various enzymes and serve as primary sites in the generation of cellular energy. Enzymes are proteins that accelerate the rate of specific chemical reactions. The term "metabolism" refers to all the chemical processes that occur within the body.
Ongoing research has determined that several metabolic disorders or inborn errors of metabolism may result in symptoms that mimic those associated with Reye syndrome (so-called "Reye-like diseases"). Metabolic disorders that may cause symptoms and findings similar to those seen in Reye Syndrome include certain urea cycle disorders (UCDs), organic acidurias, and abnormalities in fatty acid metabolism. (For information on such disorders, please see the "Related Disorders" section of this report below.)
Reye syndrome is a rare disorder that appears to affect males and females in relatively equal numbers. The disorder occurs almost exclusively in individuals younger than age 18 years. Most cases occur at about age 6, with most affected individuals ranging in age from approximately four to 12 years. However, there have been rare instances in which Reye syndrome has affected infants and young adults. Evidence suggests that children and adolescents in rural and suburban areas appear to be affected more frequently than those in urban areas.
The disorder was originally recognized as a distinct disease entity in 1963, when several cases were reported from the United States and Australia. Surveillance of Reye syndrome has indicated that the disorder tends to occur in outbreaks in association with viral infection (e.g., influenza B, varicella, various other viral infections) or may occasionally occur on a more sporadic basis, also in association with such viral infections.
The incidence of the disorder has dramatically declined in the United States beginning in the late 1980s. Approximately 200 to 550 cases were reported each year in the United States during 1974 to 1984. However, since 1988, fewer than 20 cases have been reported annually. Many researchers attribute the decline to increased public awareness concerning the potential association between Reye syndrome and the use of aspirin-containing preparations for certain viral infections and the recognition that some children suspected of having Reye syndrome actually have an inborn error of metabolism. Similar decreases in incidence rates have also been reported in the United Kingdom after public health warnings were issued.
Symptoms of the following disorders may be similar to those of Reye syndrome. Comparisons may be useful for a differential diagnosis:
Ornithine transcarbamylase (OTC) deficiency is a rare inborn error of metabolism that is classified as a urea cycle disorder. In individuals with the disorder, deficient activity of the OTC enzyme may lead to excessive amounts of ammonia in the blood (hyperammonemia). (Ammonia, a byproduct of protein metabolism, may be toxic to the brain. During a complex series of enzyme reactions within the liver known as the "urea cycle," ammonia is normally converted to the waste product urea, which is then eliminated by the kidneys.) OTC Deficiency is inherited as an X-linked trait. Males who inherit a single mutated gene for the disease (hemizygous males) usually are more severely affected than female carriers (heterozygous females) and may have associated symptoms and findings at birth. Heterozygous females may have mild disease that becomes apparent during infancy or early childhood or no apparent symptoms. Those with OTC deficiency may have persistent or periodic hyperammonemia, which may be associated with lack of appetite, vomiting, and neurologic symptoms and signs. Such abnormalities may include mental confusion, agitation, impaired control of voluntary movements (ataxia), and/or drowsiness and listlessness (lethargy) that may progress to coma. (For more information on this disorder, choose "Ornithine Transcarbamylase" as your search term in the Rare Disease Database.)
Fatty acid oxidation disorders (FODs) are a group of genetic metabolic disorders that are characterized by the abnormal accumulation of fatty acids in the body. In these disorders, the body fails to break down (metabolize) complex molecules into simpler molecules. As a result, affected individuals cannot use fats for energy. Stored fat is the secondary energy source for the body (the first is glucose). When glucose runs out, the body converts stored fat for energy. The inability to break down fatty acids results in their abnormal accumulation within the body, potentially affecting any organ system of the body. Thus, the symptoms of FODs vary widely even among members of the same family. The FODs encompass many different disorders including medium chain acyl-CoA dehydrogenase (MCAD) deficiency, very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, short chain acyl-coA dehydrogenase (SCAD) deficiency, and the primary carnitine deficiency syndromes. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a rare genetic metabolic disorder characterized by a deficiency of the enzyme medium chain acyl-CoA dehydrogenase. This enzyme is found to be most active in the liver, certain white blood cells (leukocytes), and certain connective tissue cells (fibroblasts), and is necessary for the breakdown (oxidation) of certain fats (medium chain fatty acids). Failure to break down these fats can lead to the abnormal accumulation of fatty acids in the liver and the brain. Abnormally low levels of the MCAD enzyme may also hamper or interrupt other processes associated with the metabolism of fatty acids. In infants with MCAD deficiency, symptoms may include recurrent episodes of unusually low levels of a certain sugar (glucose) in the blood (hypoglycemia), lack of energy (lethargy), vomiting, and/or liver malfunction. These symptoms are most frequently triggered when an affected infant does not eat for an extended period of time (fasting). In some cases, a viral illness (e.g., upper respiratory infection) that limits food intake may cause the symptoms to occur. MCAD deficiency is the most common disease in a group of disorders that involve abnormalities of fatty acid metabolism (fatty acid oxidation disorders [FODs]). MCAD deficiency is inherited as an autosomal recessive trait. (For more information, choose "MCAD" as your search term in the Rare Disease Database.)
Glutaricaciduria I (GA I) is a metabolic disorder characterized by deficiency of the enzyme glutaryl-CoA dehydrogenase. Onset may occur after approximately two years of age, with symptoms developing gradually or occurring suddenly following infection. Affected children may develop diminished muscle tone (hypotonia) and involuntary, irregular, jerky motions associated with relatively slow, writhing movements (choreoathetosis). Such abnormalities may progress to generalized muscle stiffness (rigidity), with involuntary, repetitive, twisting movements and abnormal postures (dystonia). Associated findings often include high concentrations of the organic acid glutaric acid in the blood and urine (organic aciduria) as well as of the derivative 3-hydroxyglutaric acid in the urine. In addition, during infection or stress, affected children may develop sudden episodes of vomiting, low blood sugar levels (hypoglycemia), increased ammonia levels in the blood, enlargement of the liver (hepatomegaly), increased blood levels of certain liver enzymes, seizures, and coma. The disorder is inherited as an autosomal recessive trait. (For more information on this disorder, choose "glutaricaciduria I" as your search term in the Rare Disease Database.)
A number of other disorders and conditions may cause certain symptoms and findings similar to those associated with Reye syndrome, including additional urea cycle disorders, fatty acid oxidation disorders, organic acidurias, and other metabolic disorders; central nervous system infections, including inflammation of the brain (encephalitis) or the protective membranes covering the brain and spinal cord (meningitis); and various other disorders. (For further information, please choose the exact disease name in question as your search term in the Rare Disease Database.)
According to researchers, Reye syndrome should be suspected in any infants, children, or adolescents who experience severe, persistent vomiting in association with evidence of unexplained acute swelling of the brain. The condition may be diagnosed based upon a complete patient history, thorough clinical evaluation, characteristic physical findings, and the results of specialized laboratory tests.
Initial tests may include liver chemistry tests (AST and ALT tests) that reveal elevated levels of certain liver enzymes (e.g., aspartate transaminase [AST], alanine transaminase [ALT]) in the blood. The results of these tests are usually available within a few hours and high levels of these enzymes are strongly suggestive of Reye syndrome.
In some individuals with Reye syndrome, analysis of the cerebrospinal fluid (CSF) may confirm increased pressure. (CSF is the watery protective fluid that circulates through the brain's four cavities [ventricles], the canal containing the spinal cord [spinal canal], and the space between layers of the protective membranes [meninges] surrounding the brain and spinal cord [i.e., subarachnoid space].) In addition, blood studies typically reveal elevated levels of certain muscle enzymes (e.g., creatine kinase) and the mitochondrial enzyme glutamate dehydrogenase. There may also be significantly increased levels of ammonia in the blood (hyperammonemia), although this is a highly variable finding. (As noted above, ammonia is a byproduct of protein metabolism that may be toxic to the brain.) Blood studies may also reveal low levels of a certain blood clotting factor (hypoprothrombinemia). According to reports in the medical literature, affected individuals with significantly elevated ammonia levels in the blood and/or hypoprothrombinemia who are unresponsive to treatment with vitamin K may have an increased likelihood of progressing to coma. (For information on therapies for individuals with Reye Syndrome, see "Treatment" below.)
In those with the disorder, laboratory tests also typically reveal reduced activities of liver (hepatic) mitochondrial enzymes, such as pyruvate dehydrogenase (PDH), ornithine transcarbamylase (OTC), and carbamyl phosphate synthetase (CPS). Researchers indicate that acquired decreases in the enzyme activities of CPS and OTC may result in increased blood ammonia levels (hyperammonemia). (Both enzymes function as part of the "urea cycle" discussed above.)
Laboratory tests may also confirm reduced levels of the simple sugar glucose in the blood (hypoglycemia), particularly in young children. CSF analysis may also reveal low glucose levels (hypoglycorrhachia) reflecting hypoglycemia. According to investigators, diagnostic screening tests should be performed for young patients to help rule out or detect underlying metabolic disorders that may be present. In addition, particularly for children younger than age one to two years, liver biopsy may be advised to help eliminate or confirm underlying metabolic or toxic liver disorders. Liver biopsy involves the surgical removal (biopsy) and microscopic evaluation of small samples of liver tissue. In those with Reye syndrome, liver biopsy typically reveals the abnormal accumulation of certain fatty compounds (e.g., triglycerides) within liver cells and structural changes of liver mitochondria.
According to reports in the medical literature, the mainstays of treatment include early diagnosis; prompt administration of intensive care as required; and measures to correct metabolic abnormalities and prevent or control increased pressure between the skull and brain (intracranial pressure [ICP]) secondary to cerebral edema.
The specific therapies used may vary from case to case, depending upon disease severity and progression. For example, in children with mild disease (e.g., Grade I severity), treatment may primarily consist of close observation. However, in those with more severe disease, intensive, emergency treatment may be required. Such measures may include continual monitoring of vital functions (e.g., of blood circulation, fluid/electrolyte balances, breathing); delivery of fluids, electrolytes, and glucose via a vein (intravenously); and/or use of a respirator to assist breathing. ICP levels must also be closely monitored, and certain medications (e.g., mannitol, dexamethasone) may be administered to help control cerebral edema and reduce ICP. Additional measures may include administration of an antibiotic (neomycin) enema and an agent that promotes the removal of ammonia from the blood (e.g., lactulose); vitamin K therapy or transfusions (e.g., with platelets or fresh frozen plasma) for blood clotting abnormalities; use of a cooling blanket or other methods to help stabilize or prevent abnormally elevated body temperature (hyperthermia); and/or other measures. For some individuals with the disorder, additional symptomatic and supportive measures may also be recommended.
Researchers indicate that there appears to be a correlation between residual cognitive effects and the severity of neurologic deterioration upon the initiation of therapy. Those with mild disease (e.g., Grade I severity) usually have a complete recovery. However, individuals with more severe disease may have residual neurologic effects, such as mental retardation, difficulties with concept formation and visual and motor integration, or other associated abnormalities.
Great care must be taken in prescribing pain-killing medications for patients suspected of having had an episode of Reye syndrome. Patients and their families should review with their physicians the reasons for choosing particular pain medications.
IInformation on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Contact for additional information about Reye syndrome:
James E. Heubi, M.D.
Professor and Associate Chair for Clinical Research of Pediatrics
Associate Dean for Clinical and Translational Research
Children's Hospital Medical Center /University of Cincinnati College of Medicine
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Report last updated: 2014/04/01 00:00:00 GMT+0